Apparatus for therapeutic apheresis

ABSTRACT

Apparatus for carrying out therapeutic apheresis includes a filter device for being implanted in a blood vessel for carrying out in-vivo plasma separation having one or more elongated hollow tubes and a plurality of elongated hollow microporous fibers capable of separating plasma from whole blood at pressure and blood flow within a patient&#39;s vein, a multiple lumen catheter secured to the proximal end of the filter device having one or more lumens in fluid communication with the interior of said one or more hollow tubes and a plasma return lumen, and therapeutic apheresis apparatus for removing and/or separating selected disease-related components from the separated plasma and means for directing plasma between said catheter and the selective component removal apparatus.

RELATED APPLICATION

This application claims priority to and is a divisional of U.S.application Ser. No. 10/219,082, entitled “Method and Apparatus forTherapeutic Apheresis,” filed on Aug. 13, 2002, which is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

In the field of medicine, the term “therapeutic apheresis” refers totechniques for treating diseases using the patient's blood. Currentmedical practice extracts whole blood from the patient and, as a firststage, separates the plasma from the blood ex-vivo by centrifugal ormembrane separation, and in a second stage treats the separated plasmaby various techniques. The treated plasma and blood are recombinedex-vivo and returned to the patient. In the simplest procedure theseparated plasma including the pathogenic macromolecules is discardedand substitution fluids such as fresh frozen plasma and albumen solutionare re-infused to the patient.

In all of the aforesaid and currently practiced therapeutic apheresisprocedures, whole blood must be removed from the body and processed intwo ex-vivo stages. However, removal and treatment of whole blood hasmajor disadvantages. Whole blood removal results in the necessity toheparinize or anticoagulate the patient to minimize clotting in theex-vivo circuit and apparatus. Such treatment is counter-indicated inmost surgical patients and deleterious to others due to consequentialdamage to blood components and the removal of vital blood componentsunrelated to the therapy. Removing and treating whole blood ex-vivodictates that the procedure be a “batch” or intermittent process withattendant loss of efficiency and confinement of the patient to aclinical setting where support systems and machinery are available.Removal of whole blood also exposes the patient to contamination byviral and/or bacterial infection from nosocomial sources, and removal oferythrocytes, platelets and other large cellular blood componentsexposes them to risk of damage due to mechanical and chemical exposureto non-biocompatible surfaces of ex-vivo apparatus.

SUMMARY OF THE INVENTION

The present invention relates to methods and apparatus for carrying outtherapeutic apheresis. In the present invention, plasma, not wholeblood, is removed from the patient in a first stage of therapeuticapheresis. Plasma separation is performed in-vivo by a plasma separationfilter placed in an appropriate vein and the separated plasma is pumpedto a therapeutic apheresis selective component removal system forseparating and removing selected disease-related plasma components orplasma containing such components such as toxins, antibodies, proteins,bacteria, and/or viruses. After the appropriate disease-related plasmacomponent is extracted by the therapeutic apheresis apparatus, theprocessed plasma, and if desired fresh plasma, is pumped to the patient.

In a preferred embodiment, a system used for carrying out therapeuticapheresis comprises apparatus including a filter device for beingimplanted in a blood vessel for in-vivo plasma separation incorporatinga plurality of elongated microporous hollow fibers having anasymmetrical fiber wall morphology in which the inner wall surface alongthe interior fiber lumen has a lower mass density and the fiber walladjacent to the outer wall surface has a higher mass density. Apreferred filter device comprises one or more elongated hollow tubes towhich opposite ends of each of the fibers are secured so that theinterior of the one or more hollow tubes communicates with the interiorof each of the elongated hollow fibers. The system includes a triplelumen catheter, secured to a proximal end of the one or more hollowtubes for directing blood plasma passing through the fiber walls andinto the fiber lumen to therapeutic apheresis selective componentremoval apparatus. The system also includes fluid control piping andcooperating pumps for directing plasma between system components. Thesystem includes backflush components comprising piping, backflush pumpand source of backflush fluid selectively directed to the filter devicefor a duration and flow rate sufficient to substantially cleanse filterpores. In a preferred embodiment, operation of the system is controlledby a microprocessor/controller.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a preferred embodiment ofapparatus for carrying out therapeutic apheresis;

FIG. 2 schematically illustrates one embodiment of therapeutic apheresisapparatus using plasma exchange;

FIG. 3 schematically illustrates a therapeutic apheresis apparatusembodiment using double, cascade filtration;

FIG. 4 is a top view of a preferred embodiment of a filter device shownin FIG. 1 for separating plasma from blood in-vivo having a pair ofelongated substantially parallel hollow tubes joined together alongtheir length, showing distal and proximal end segments;

FIG. 5 is an enlarged sectional view of the filter device of FIG. 3along the lines A-A showing a single elongated hollow fiber secured tothe hollow tubes;

FIG. 6 is a sectional view of a triple lumen catheter of the apparatusshown in FIG. 1 illustrating the catheter interior; and

FIG. 7 is a scanning electron microscopy (SEM) image of a cross-sectionof a preferred elongated hollow fiber used in a filter device shown inFIG. 3 at 400 μm magnification.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred embodiment of an apparatus for carrying out therapeuticapheresis according to the invention schematically illustrated in FIG. 1includes a filter device 10, a triple lumen catheter 20, a therapeuticapheresis selective component removal apparatus 40, a fluid controlassembly including tubing and pumps, and a microprocessor/controller 30.The filter device 10, which will be described in more detailhereinafter, is implantable in the vasculature of a patient or animal inwhich in-vivo plasma separation is to be carried out. Veins suitable forimplanting the filter include the superior or inferior vena cava or thesubclavian vein. In the drawing, the filter device 10 is shown implantedin the inferior vena cava 15. A triple lumen catheter 20 is secured tothe proximal end 11 of the filter with header 14. Triple lumen catheter20 is in fluid communication with the interior of the filter device withthe three catheter lumens connected to tubing for directing outgoingplasma, return plasma, and backflush fluid. Referring also to FIGS. 4-6,plasma separated from whole blood through the microporous fibers 12 ofthe filter device are directed through access lumen 21 and first tubing31 to selective component apparatus 40. Plasma is separated from wholeblood within the blood vessel in which the filter device is insertedusing trans-membrane pressure (TMP) supplied by access pump or firstpump 34, a positive displacement volumetric pump that operates toregulate pressure and control trans-membrane pressure and plasma volumeremoval rate.

Plasma from the filter device is pumped to the therapeutic apheresisselective component removal apparatus 40 for selectively removingdisease-related components such as toxins, antibodies, proteins,pathogens including bacteria, virus, etc., and other disease-relatedsubstances desired to be removed. Plasma components and solutes removedfrom the treated plasma are directed to a container 44. An effluent pump42 is optional and may be advantageously used for assisting incontrolling the rate of disease components removed by providingcontrolled trans-membrane pressure across filter membranes of theselective component removal apparatus. Plasma is returned to the patientvia tubing 43 at a rate controlled by pump 36. The tubing 43 is in fluidcommunication with plasma return tube 32 which is connected to plasmareturn lumen 22 of triple lumen catheter 20 (FIG. 5).

Examples of selective component removal apparatus used for therapeuticapheresis include plasma exchange components, centrifugal ormembrane-separation filters, such as disclosed in U.S. Pat. No.5,605,627, cascade or multiple filtration membranes and columns,cartridges having components for absorbing (adsorbing) specificdisease-related components, and activated charcoal cartridges. Otherexamples of useful selective component removal components includespecialized columns utilizing materials such as cross-linked polyvinylalcohol gel beads or microporous cellulose beads for removing specificamino acid ligands and antibodies. Further examples of selectivecomponent removal apparatus are chemical process systems for specializeduses such as heparin precipitation, plasma cyrofiltration, andsalt-amino acid co-precipitation, and the like. Chemical processapparatus for effectively neutralizing disease related components in theplasma may also be used. These and other selective component removalapparatus and technologies are described in Therapeutic Apheresis,Official Journal of the International Society for Apheresis, Vol. 1-6,Blackwell Science Inc., “Present Status of Apherisis Technologies”, e.g.Vol. 1, No. 2, May, 1997, pp. 135-146, the descriptions of which areincorporated herein by reference. Combinations of two or more of any ofthe aforesaid apparatus may also be used.

FIG. 2 illustrates a plasma exchange apparatus 45 for separating plasmacomponents and for delivering fresh plasma from supply source 49. Theplasma exchange rate may be selected as a function of the plasma removalrate by proportioning the rate of operation of access pump 34 toeffluent pump 42, as shown in FIG. 1.

FIG. 3 schematically illustrates an example of selective componentremoval apparatus showing a cascade filter comprising a first stagefilter 46 and a second stage filter 47. A pump 48 is used for directingfluid plasma from the first stage filter to the second stage filter. Asource of make-up plasma liquid 49 may be used, if desired, forintroducing substitution fluids such as fresh plasma which is combinedwith the treated plasma to be returned to the patient via tubing 41 and43. Container 44 receives and collects discarded plasma fluid containingdisease-related components, such as toxins, etc. as previouslydescribed. In a single stage treatment apparatus, the use of a make-upplasma liquid is also optional as is effluent pump 42 shown in FIG. 1and cooperating with selective component removal apparatus 40 fordirecting fluid and components to be discarded. Again, followingtreatment in selective component removal apparatus 40, plasma isreturned to the patient via piping 43 and positive displacement pump 36to plasma return tube 32 which is in fluid communication with plasmareturn lumen 22 of triple lumen catheter 20 (see FIG. 6).

An apparatus using cartridges or columns for absorbing or adsorbingdisease-related components may also be used for treating separatedplasma. Such apparatus may be configured like or similar to thatillustrated in FIGS. 2 and 3 in which the columns shown incorporateabsorbing or adsorbing filters comprising materials capable of absorbingselected disease-related components such as discussed herein. Again,such an apparatus may include a source of fresh plasma to be directed tothe patient, if desired.

The preferred apparatus shown in FIG. 1 includes backflush fluidreservoir 37, backflush pump 38 and backflush tube 33 communicating witha backflush lumen of the triple lumen catheter. Such backflushcomponents and method are disclosed in U.S. Pat. No. 6,659,973, thedescriptions of which are incorporated herein by reference. Backflushpump 38 is selectively and periodically operated to provide backflushfluid flow for substantially cleansing the pores of the fiber membraneof the filter device. Such a backflush cycle is preferably operated athigh trans-membrane pressure and low volume and at relatively shortinjection times for backflushing whereby the membrane pores aretemporarily expanded and flushed to dislodge adhered proteins, therebyrestoring pore integrity and density of the virtual filter area forimproved performance after each backflush cycle.

Fluid control of plasma within the apparatus may be controlled using amicroprocessor/controller operatively communicating with the positivedisplacement volumetric pumps for controlling trans-membrane pressure inthe filter device and selective component removal apparatus, plasmaremoval rate, plasma return rate and backflush pressure and rate. Suchfluid control and management may be selected, tailored or designed forslow, continuous acute fluid removal. For example, operation of thesystem may be used for controlling plasma extraction rate from blood toachieve removal of 1-2 L of plasma water over a 24-hour period. Thefluid control assembly may also include volume sensors, pressuresensors, blood leak detectors and air detectors connected to the pipingand reservoirs as desired. As illustrated in FIG. 1, themicroprocessor/controller 30 is operatively connected to the pumps.Similarly, the microprocessor/controller operates for controllingbackflush pump 38 and plasma is returned at a selected rate bycontrolling pump 36. The microprocessor/controller may be programmed forflow rates designed to a the prescribed patient therapy.

In a preferred embodiment of the filter device 10 illustrated in FIGS.1, 4 and 5, a pair of elongated hollow tubes are joined side-by-sidelengthwise to form the core of the filter device. The two elongatedhollow core tubes 16 and 18 terminate at a distal end with a distal endplug or cap 13 formed of a material that seals the open tube ends. Thetubes and end cap may be made of any suitable biocompatible material,for example, medical grade extruded urethane tubes. Other biocompatiblematerials include synthetic rubbers, polycarbonate, polyethylene,polypropylene, nylon, etc. The elongated hollow tubes may be securedtogether using suitable bonding material 24, adhesive composition, etc.,for example, a UV curable adhesive applied along the length between thetwo tubes. The length and diameter of the filter device may be selectedto accommodate the vessel or vein in which it is to be implanted.Accordingly, the diameter and length of the one or more elongated hollowtubes forming the central core of the filter device are selected. Asuitable tube length is between about 15 cm and about 25 cm, andpreferably between about 18 cm and about 22 cm. Where a pair of coretubes is used as shown in the preferred embodiment, an outer diameter ofeach tube of between about 1 mm and about 3 mm is suitable. A detectablemarker component 26, e.g., a radio opaque material, may also be bondedto the device, for example, in bonding material 24 extending along thelength of the tubes to assist in implanting and/or monitoring the deviceduring insertion, use and removal.

Effective plasma separation is also a function of fiber length. Thus,the length of the individual hollow fibers is preferably less than about5 mm and preferably between about 1 mm an about 4 mm. Moreover, fiberorientation relative to blood flow within the vessel is also ofsignificant importance. Preferably, the fibers are aligned so that thelongitudinal fiber axis is between about 45° and about 90° relative tothe direction of blood flow. The filtration performance of a filterdevice to separate plasma from whole blood in-vivo is also a function ofthe filter surface of the exposed fibers whereby consideration is givento use larger diameter fibers and to maximize the number of fibers. Itis desirable to use as many individual fibers along the hollow coretubes of the filter device as is practical while maintaining separationof the individual fibers to provide for fluid flow therebetween, and tomaximize the amount of outer fiber surface exposed to blood flowingalong the length of the filter device. Moreover, the fibers are securedalong the length of the hollow tubes in such a manner as to form a fluidflow space between the fibers and the tubes. The length of the filterdevice as well as the overall cross-sectional dimension are tailored ordictated by the blood vessel in which the device is to be used so as toavoid substantial interference with blood flow through the vessel whileat the same time be efficient to achieve the intended flow rate ofseparated plasma.

Preferably, the ends of each of the fibers are offset longitudinallyrelative to one another. Referring to FIGS. 4 and 5, elongated hollowfiber 12 has a first end 17 secured in first elongated hollow tube 16and second end 19 secured in second hollow tube 18. In the specificdevice illustrated, the longitudinal spacing between the first andsecond ends of each fiber is a three-hole or three-fiber offset, e.g.,about 0.5 cm. However, with intervals between the adjacent fiber ends ofbetween about 0.1 cm and about 1.0 cm, offsets between first and secondfiber ends may be between about 0.3 cm and about 3.0 cm, by way ofexample. With such offsets between first and second fiber ends, astraight line extending between the ends of a fiber forms an acute anglewith an elongated axis of either or both of the elongated hollow tubes,and whereby the fibers also extend lengthwise between their ends alongan angle other than 90° relative to the axes of the elongated hollowtubes. The acute angle preferably is between about 45° and about 85°.However, other fiber angles including 90° are not precluded and may beused where desired. Such fiber angles provide desirable fiberorientation relative to blood flow as previously described. Other filterdevice embodiments which may be used are disclosed in copendingapplication Ser. No. 09/981,783 filed Oct. 17, 2001 (TRANSVI.011A), thedescriptions of which are incorporated herein by reference.

Conventional hollow fibers or filter membranes such as those used inconventional dialysate filter devices are unable to successfully performin-vivo, intravascular plasma separation, becoming clogged within a veryshort period of time, e.g., minutes, as proteinaceous materials, bloodplatelets, and other components rapidly occlude the membrane pores.Conventional dialysate filter membranes have little structural strengthwhich, although acceptable in an encapsulated dialysate filterenvironment external to the body, are not suitable for intravascularuse. Moreover, conventional dialysate hollow fiber membrane filters donot perform satisfactorily in-vivo because of the relatively high flowrate of blood at the exterior fiber surface and relatively low lumenpressure as compared to dialysate filter apparatus conditions in whichplasma separation is carried out at relatively low flow rates and hightrans-membrane pressures. For example, typical in-vivo blood flow withina vena cava is about 2.5 L per minute, while blood flow through typicaldialysate filter apparatus is nearly stagnant, e.g., about 0.42 ml perminute per fiber. Intravascular trans-membrane pressure is typicallyabout 50 mm Hg or less, as compared to 100-300 mm Hg used inextracorporeal dialysate filters.

The preferred elongated hollow microporous fibers used in the filterdevice described herein are the asymmetrical wall fibers disclosed inU.S. Pat. No. 6,802,820, the descriptions of which are incorporatedherein by reference. The fiber wall structure of the elongatedmicroporous fibers is asymmetrical between the inner wall surfaceextending along the interior fiber lumen and the outer fiber wallsurface exposed to blood in the vessel in which the filter device isimplanted. The fiber wall at or adjacent to the outer wall surface has ahigher mass density than the mass density adjacent to or at the innerwall surface. The mass density is a function of the average nominal poresize. Such asymmetric fiber wall morphology is illustrated in FIG. 7showing a scanning electron microscopy (SEM) image of a cross-section ofthe fiber at 400 μm magnification. It will be observed that thestructure of the fiber from the outer surface to the lumen is acontinuous change in mass density whereby the pore size graduallychanges between these fiber wall surfaces. The fiber walls are alsocharacterized by a substantially uniform wall thickness between theinner and outer wall surfaces and have substantially no macrovoids otherthan the pores, as shown. It is convenient to describe the continuum ofdifferent mass density as sections or zones of the wall area having anaverage nominal pore size or average pore diameter, each zone having adifferent average nominal pore size. Thus, the walls may becharacterized by two or more zones, for example 2, 3, or 4 or more massdensity zones. The hollow fiber shown in FIG. 7 is also shown anddescribed in the aforesaid Pat. No. 6,802,820.

The advantages which may be accrued by using the therapeutic apheresismethods and apparatus described above include elimination of thedisadvantages of the removal of whole blood from the body and subsequentex-vivo plasma separation as previously described. In-vivo plasmaseparation permits continuous real time therapy in most applicationswith resultant improvement in effectiveness, and in many applicationswould result in the ability to perform the therapy in a home setting orambulatory mode which could be a major improvement in patient lifestyleas well as economy for the medical care system. Moreover, the use of themethods and apparatus described herein would increase the capacity ofmost caregiver organizations which are now limited by patient loadcapacity including the number of centrifuge machines available in thefacility.

Examples of diseases and disorders for which therapeutic apheresis maybe used and the pathogenic substances removed using the methods andapparatus of the invention include those listed in Exhibit 1, anddescribed in Therapeutic Apherisis, Vol. 1, No. 2, 1997. The list is notintended to be exhaustive, and other diseases and substances may also betreated. Moreover, the methods and apparatus described herein may alsobe used in drug treatment, for example in drug overdose cases, where oneor more toxic substances in the blood stream may be removed using theaforesaid methods and apparatus. These as well as others advantages willbe evident to those skilled in the art.

1. Apparatus for carrying out therapeutic apheresis comprising: animplantable filter device comprising one or more elongated hollow tubesand a plurality of elongated microporous fibers capable of separatingplasma from whole blood in-vivo, each fiber having an interior lumenextending along the length thereof and having a first and second endsecured to one or more of said elongated hollow tubes wherein theinterior lumen of each of the fibers communicates with the interior ofone or more of the hollow tubes; a triple lumen catheter secured to theproximal end of the filter device having one or more lumens in fluidcommunication with the interior of said one or more hollow tubes and aplasma return lumen; and therapeutic apheresis apparatus for removingand/or separating selected disease-related components from the separatedplasma and tubing for directing plasma between said catheter and theselective component removal apparatus.
 2. Apparatus of claim 1 whereinsaid triple lumen catheter comprises a first lumen and a second lumen influid communication with the interior of said one or more hollow tubesand a third lumen comprising said plasma return lumen.
 3. Apparatus ofclaim 1 wherein said therapeutic apheresis apparatus comprises a plasmaexchange assembly.
 4. Apparatus of claim 1 wherein said therapeuticapheresis apparatus comprises a multiple stage filtration assembly. 5.Apparatus of claim 1 wherein said therapeutic apheresis apparatuscomprises one or more columns or cartridges containing materials forabsorbing disease-related components passing therethrough.
 6. Apparatusof claim 1 wherein said selective component removal apparatus comprisesone or more reactors containing compositions for reacting withdisease-related components in the plasma.
 7. Apparatus of claim 1including: a fluid control assembly comprising first tubing in fluidcommunication with said first lumen of said catheter and a first fluidpump cooperating therewith for directing plasma from said filter device,second tubing in fluid communication with said second lumen of saidcatheter and a second pump cooperating therewith for directing backflushfluid into said filter device, and third tubing in fluid communicationwith said third lumen of said catheter for directing plasma from thetherapeutic apheresis apparatus to a patient; and control apparatusoperatively communicating with said first and second pumps forcontrolling the operation thereof, respectively.
 8. Apparatus of claim 7including a third pump cooperating with said third tubing and in controlconnection with said control apparatus.
 9. Apparatus of claim 7including a source of backflush fluid cooperating with said secondtubing.
 10. Apparatus of claim 7 wherein said control apparatuscomprises a microprocessor-controller including software programmed foroperating one or more of said pumps.
 11. Apparatus of claim 8 whereinsaid control apparatus comprises a microprocessor-controller includingsoftware programmed for operating one or more of said pumps. 12.Apparatus of claim 9 wherein said control apparatus comprises amicroprocessor-controller including software programmed for operatingone or more of said pumps.
 13. Apparatus of claim 1 wherein said filterdevice comprises first and second elongated hollow tubes extendingsubstantially parallel along the length thereof, and wherein a first endof each of said elongated microporous fibers is secured to a firsthollow tube and a second end of each of said fibers is secured to asecond hollow tube whereby the interior fiber lumen of each fibercommunicates with the interior of a first and a second hollow tube. 14.Apparatus of claim 13 wherein the first hollow tube extends along afirst axis and the second hollow tube extends along a second axissubstantially parallel with said first axis, and wherein the first endsof said elongated microporous fibers are secured to said first hollowtube along a generally straight first row, and the second ends of saidelongated microporous fibers are secured to said second hollow tubealong a generally straight second row substantially parallel with saidfirst row.
 15. Apparatus of claim 14 wherein each of said fibers aregenerally bowed along its length between said first and second ends toform an arch spaced apart from said elongated hollow tubes and forming apassageway therebetween.
 16. Apparatus of claim 13 wherein the first andsecond ends of said elongated microporous fibers are secured to saidfirst and second hollow tubes, respectively, at substantially regularintervals.
 17. Apparatus of claim 14 wherein said regular intervals arebetween about 0.1 cm and about 1.0 cm.
 18. Apparatus of claim 1 whereinthe length of each of said elongated microporous fibers is between about1 cm and about 4 cm.
 19. Apparatus of claim 13 wherein the length ofeach of said elongated microporous fibers is between about 1 cm andabout 4 cm.
 20. Apparatus of claim 14 wherein the length of each of saidelongated microporous fibers is between about 1 cm and about 4 cm. 21.Apparatus of claim 14 wherein the first end of each elongatedmicroporous fiber is offset longitudinally from the second end of eachsaid fiber along the length of said elongated hollow tubes whereby astraight line extending through the first and second end of a fiberforms an acute angle with one of said axes.
 22. Apparatus of claim 21wherein the length of each hollow tube is between about 10 cm and about25 cm, wherein the length of each elongated microporous fiber is betweenabout 1 mm and about 4 mm, wherein the space between adjacent fibers isbetween about 0.1 cm and about 0.3 cm, and wherein said acute angle isbetween about 45° and about 85°.
 23. Apparatus of claim 1 wherein thefiber wall morphology of the elongated microporous fibers isasymmetrical between the inner wall surface extending along the interiorfiber lumen and the outer wall surface, said fiber wall having a highermass density zone adjacent to the outer wall surface and a lower massdensity zone adjacent to the inner wall surface, said higher massdensity zone having a smaller average nominal pore size than the averagenominal pore size of the lower mass density zone.
 24. Apparatus of claim23 wherein the fiber wall structure comprises a continuous change inmass density between the inner and outer surfaces of the fiber. 25.Apparatus of claim 7 including a container cooperating with saidtherapeutic apheresis apparatus for receiving effluent therefrom. 26.Apparatus of claim 25 including fourth tubing in fluid communicationwith said container and said therapeutic apheresis apparatus. 27.Apparatus of claim 26 including an effluent pump cooperating with saidfourth tubing for pumping effluent from said therapeutic apheresisapparatus to said container.
 28. Apparatus of claim 27 including controlconnection between said control apparatus and said effluent pump. 29.Apparatus of claim 28 wherein said control apparatus comprises a programfor directing operation of said apparatus.
 30. Apparatus of claim 28wherein said control apparatus comprises a program for controllingoperation of one or more of said pumps.
 31. Apparatus of claim 28wherein said control apparatus comprises a microprocessor-controllerincluding a program for controlling operation of one or more of saidpumps.